Cortical Pain Responses Research Articles

Impact of breast milk on cortical pain response in newborns during the heel prick procedure: a randomized controlled trial

ObjectiveTo investigate the effects of breast milk on cortical pain response and behavioral response in newborns during heel-prick procedure.Study designA prospective, randomized controlled trial was conducted on healty-term newborns, undergoing heel blood sampling. Infants were randomly assigned to study group with receive orally 2 ml breast milk (n = 45) or a control group with no intervention (n = 45). A near-infrared spectroscopy device was used to monitor regional cerebral oxygen saturation (rScO2), while neonatal pain expression was assessed by Neonatal Pain, Agitation, and Sedation Scale (N-PASS).ResultsThe N-PASS score (p = 0.001) and the crying time (p = 0.017) were significantly lower in the study group compared to the control group. Although the mean rScO2 values decreased in both groups during the procedure, the percent change in rScO2 was not significant difference between two groups.ConclusionBreast milk administration decreases behavioral responses to a noxious stimulus without reducing the cortical response to pain.Clinical trial registrationThis trial was registered under ClinicalTrials.gov identifier no. NCT05961904.

Clinical thresholds in pain-related facial activity linked to differences in cortical network activation in neonates.

In neonates, a noxious stimulus elicits pain-related facial expression changes and distinct brain activity as measured by electroencephalography, but past research has revealed an inconsistent relationship between these responses. Facial activity is the most commonly used index of neonatal pain in clinical settings, with clinical thresholds determining if analgesia should be provided; however, we do not know if these thresholds are associated with differences in how the neonatal brain processes a noxious stimulus. The objective of this study was to examine whether subclinical vs clinically significant levels of pain-related facial activity are related to differences in the pattern of nociceptive brain activity in preterm and term neonates. We recorded whole-head electroencephalography and video in 78 neonates (0-14 days postnatal age) after a clinically required heel lance. Using an optimal constellation of Neonatal Facial Coding System actions (brow bulge, eye squeeze, and nasolabial furrow), we compared the serial network engagement (microstates) between neonates with and without clinically significant pain behaviour. Results revealed a sequence of nociceptive cortical network activation that was independent of pain-related behavior; however, a separate but interleaved sequence of early activity was related to the magnitude of the immediate behavioural response. Importantly, the degree of pain-related behavior is related to how the brain processes a stimulus and not simply the degree of cortical activation. This suggests that neonates who exhibit clinically significant pain behaviours process the stimulus differently and that neonatal pain-related behaviours reflect just a portion of the overall cortical pain response.

Pharmacological restoration of anti-nociceptive functions in the prefrontal cortex relieves chronic pain.

Chronic pain affects one in four adults, and effective non-sedating and non-addictive treatments are urgently needed. Chronic pain causes maladaptive changes in the cerebral cortex, which can lead to impaired endogenous nociceptive processing. However, it is not yet clear if drugs that restore endogenous cortical regulation could provide an effective therapeutic strategy for chronic pain. Here, we studied the nociceptive response of neurons in the prelimbic region of the prefrontal cortex (PL-PFC) in freely behaving rats using a spared nerve injury (SNI) model of chronic pain, and the impact of AMPAkines, a class of drugs that increase central glutamate signaling, on such response. We found that neurons in the PL-PFC increase their firing rates in response to noxious stimulations; chronic neuropathic pain, however, suppressed this important cortical pain response. Meanwhile, CX546, a well-known AMPAkine, restored the anti-nociceptive response of PL-PFC neurons in the chronic pain condition. In addition, both systemic administration and direct delivery of CX546 into the PL-PFC inhibited symptoms of chronic pain, whereas optogenetic inactivation of the PFC neurons or administration of AMPA receptor antagonists in the PL-PFC blocked the anti-nociceptive effects of CX546. These results indicate that restoration of the endogenous anti-nociceptive functions in the PL-PFC by pharmacological agents such as AMPAkines constitutes a successful strategy to treat chronic neuropathic pain.

Characterization of cortical source generators based on electroencephalography during tonic pain.

ObjectiveThe aim of the present study was to characterize the cortical source generators evoked by experimental tonic pain.MethodsElectroencephalography (EEG) was recorded on two separate days during rest and with immersion of the hand in ice water for 2 minutes (cold pressor test). Exact low-resolution brain electromagnetic tomography source localization was performed in 31 healthy volunteers to characterize the cortical source generators.ResultsReliability was high in all eight frequency bands during rest and cold pressor conditions (intraclass coefficients =0.47–0.83 in the cingulate and insula). Tonic pain increased cortical activities in the delta (1–4 Hz), theta (4–8 Hz), beta1 (12–18 Hz), beta2 (18–24 Hz), beta3 (24–32 Hz), and gamma (32–60 Hz) bands (all P<0.011) in widespread areas mainly in the limbic system, whereas decreased cortical activities were found in cingulate and pre- and postcentral gyri in the alpha2 (10–12 Hz) band (P=0.007). The pain intensity was correlated with cingulate activity in the beta2, beta3, and gamma bands (all P<0.04).ConclusionSource localization of EEG is a reliable method to estimate cortical source generators. Activities in different brain regions, mainly in the limbic system, showed fluctuations in various frequency bands. Cingulate changes were correlated with pain intensity.SignificanceThis method might add information to the objective assessment of the cortical pain response in future experimental pain studies.

PS-195 Sucrose Versus Breastfeeding For Venipuncture In Term Infants. A Randomised, Prospective, Controlled Study With Analysis Of The Specific Cortical Response

Background and aims Sucrose and breast milk during painful procedures are reported to decrease pain behavioural expression in neonates. Recent data showed a persistent cortical pain response while using the sucrose during a painful procedure. To compare the efficacy of sucrose versus breast milk for specific-pain brain activity relief during a painful procedure in neonates. Methods Randomised, prospective, controlled study. Each term newborn was randomly assigned to sucrose or breastfeeding group at day 3 during a systematic venipuncture. Change in the total haemoglobin concentration in the controlateral somatosensory cortex (Near Infra-red Spectroscoy, NIRS) was assessed 10 seconds before and after the venipuncture. Neonatal Facial Coding System (NFCS) was assessed 2 min before and at the time of the venipuncture. Groups were compared using Wilcoxon test for the variations in NIRS and Chi-square test for the NFCS scores. Results 113 newborns were included (sucrose: 56, breastfeeding: 57) with a mean (sd) of 39.3 weeks (0.9) for gestational age and 3370 g (478) for birth weight. 103 were analysed for the NIRS (sucrose: 55, breastfeeding: 48). Median (quartiles) of total haemoglobin concentration change was -8.5 µmol/L (-34.5; 12.5) for sucrose group and 12.3 µmol/L (-23.4; 39.3) for breastfeeding group with no statistical difference (p = 0.06). NFCS scores were significantly different with 46.8% with a painful score in the breastfeeding versus 26.8% in the sucrose (p = 0.03). Conclusions No difference were found between sucrose and breastfeeding on specific-pain brain activity during a venipuncture in term newborns. A discordance was revealed between NFCS scores and NIRS analysis.

Facilitation of Pain in the Human Spinal Cord by Nocebo Treatment

Nocebo hyperalgesia is an increase in subjective pain perception after a patient or subject underwent an inert treatment without any active ingredient. For example, verbal suggestion of increased pain can enhance both pain experience and responses in pain-related cortical brain areas. However, changes in cortical pain responses may be secondary to earlier amplification of incoming pain signals within the spinal cord. To test for a potential early enhancement of pain signals in the dorsal horn of the spinal cord, we combined a nocebo heat pain paradigm with spinal functional magnetic resonance imaging in healthy volunteers. We found that local application of an inert nocebo cream on the forearm increased pain ratings compared with a control cream, and also reduced pain thresholds on the nocebo-treated skin patch. On the neurobiological level, pain stimulation induced a strong activation in the spinal cord at the level of the stimulated dermatomes C5/C6. Comparing pain stimulation under nocebo to a control pain stimulation of the same physical intensity revealed enhanced pain-related activity in the ipsilateral dorsal horn of the spinal cord. Importantly, the activation of the main effect of pain and the nocebo effect spatially overlapped. The current study thus provides direct evidence for a pain-facilitating mechanism in the human spinal cord before cortical processing, which can be activated by cognitive manipulations such as nocebo treatments.

192 Analgesia Modulates Cortical Response to Painful Procedures in Extremely Preterm Newborn Infants

IntroductionProper pain management in the neonatal intensive care unit (NICU) is essential. The clinical pain assessment depends on objective measurement of indirect behavioural and physiological pain indicators. Cortical pain processing...

Cerebral Near-Infrared Spectroscopy as a Measure of Nociceptive Evoked Activity in Critically III Infants

Signs of pain may be subtle or absent in a critically ill infant. The complex nature of pain may further obscure its identification and measurement. Because the use of monitoring and neuroimaging techniques has become more common in pain research, an understanding of these specialized technologies is important. Near-infrared spectroscopy (NIRS) is a noninvasive technique for monitoring tissue hemodynamics and oxygenation. There are indications that NIRS is capable of detecting the cerebral hemodynamic changes associated with sensory stimuli, including pain, in infants. These developments suggest that NIRS may play an important role in research focusing on pain perception in critically ill infants. The present review briefly describes the cortical responses to noxious stimuli, which parallel cerebral hemodynamic responses to various stimuli. This is followed by an overview of NIRS technology including a summary of the literature on functional studies that have used NIRS in infants. Current NIRS techniques have well-recognized limitations that must be considered carefully during the measurement and interpretation of the signals. Nonetheless, until more advanced NIRS techniques emerge, the current devices have strengths that should be exploited.

Influence of repeated painful procedures on prefrontal cortical pain responses in newborns

We examined whether previous experience of repeated skin punctures altered the correlation between prefrontal cortical pain responses and Premature Infant Pain Profile (PIPP) scores, compared with infants who had no experience of skin puncture. Eighty infants at 37-42 weeks of gestational age were observed during clinically required blood sampling: full-term infants with no experience of painful skin-breaking procedures before data collection (controls; n = 30), full-term infants with the experience of painful skin-breaking procedures (n = 20) and preterm infants with the experience of painful skin-breaking procedures (n = 30). We found no significant differences in PIPP scores among groups. In controls, prefrontal activation in both hemispheres correlated with facial expression score of the PIPP (r = 0.53 for right prefrontal area; r = 0.37 for left prefrontal area) and the total score. In full-term infants with the experience of pain, there was no correlation between cortical activation and clinical pain scores. In preterm infants, prefrontal activation in both hemispheres correlated with the physiological component of the PIPP score (r = 0.36 for right prefrontal area; r = 0.41 for left prefrontal area). Our findings may be useful in considering the effects of cumulative painful experience on emotion and stress in neonates.

Cortical Pain Responses in Human Infants

Despite the recent increase in our understanding of the development of pain processing, it is still not known whether premature infants are capable of processing pain at a cortical level. In this study, changes in cerebral oxygenation over the somatosensory cortex were measured in response to noxious stimulation using real-time near-infrared spectroscopy in 18 infants aged between 25 and 45 weeks postmenstrual age. The noxious stimuli were heel lances performed for routine blood sampling; no blood tests were performed solely for the purpose of the study. Noxious stimulation produced a clear cortical response, measured as an increase in total hemoglobin concentration [HbT] in the contralateral somatosensory cortex, from 25 weeks (mean Delta[HbT] = 7.74 micromol/L; SE, 1.10). Cortical responses were significantly greater in awake compared with sleeping infants, with a mean difference of 6.63 micromol/L [95% confidence interval (CI) limits: 2.35, 10.91 micromol/L; mean age, 35.2 weeks]. In awake infants, the response in the contralateral somatosensory cortex increased with age (regression coefficient, 0.698 micromol/L/week; 95% CI limits: 0.132, 1.265 micromol/L/week) and the latency decreased with age (regression coefficient, -0.9861 micromol/L/week; 95% CI limits: -1.5361, -0.4361 micromol/L/week; age range, 25-38 weeks). The response was modality specific because no response was detected after non-noxious stimulation of the heel, even when accompanied by reflex withdrawal of the foot. We conclude that noxious information is transmitted to the preterm infant cortex from 25 weeks, highlighting the potential for both higher-level pain processing and pain-induced plasticity in the human brain from a very early age.

Cortical Pain Response Differs in IBS Patients

Cortical Pain Response Differs in IBS Patients

Abnormal forebrain activity in functional bowel disorder patients with chronic pain

Abnormal cortical pain responses in patients with fibromyalgia and conversion disorder raise the possibility of a neurobiologic basis underlying so-called "functional" chronic pain. To use percept-related fMRI to test the hypothesis that patients with a painful functional bowel disorder do not process visceral input or sensations normally or effectively at the cortical level. Eleven healthy subjects and nine patients with irritable bowel syndrome (IBS) underwent fMRI during rectal distensions that elicited either a moderate level of urge to defecate or pain. Subjects continuously rated their rectal stimulus-evoked urge or pain sensations during fMRI acquisition. fMRI data were interrogated for activity related to stimulus presence and to specific sensations. In IBS, abnormal responses associated with rectal-evoked sensations were identified in five brain regions. In primary sensory cortex, there were urge-related responses in the IBS but not control group. In the medial thalamus and hippocampus, there were pain-related responses in the IBS but not control group. However, pronounced urge- and pain-related activations were present in the right anterior insula and the right anterior cingulate cortex in the control group but not the IBS group. Percept-related fMRI revealed abnormal urge- and pain-related forebrain activity during rectal distension in patients with irritable bowel syndrome (IBS). As visceral stimulation evokes pain and triggers unconscious processes related to homeostasis and reflexes, abnormal brain responses in IBS may reflect the sensory symptoms of rectal pain and hypersensitivity, visceromotor dysfunction, and abnormal interoceptive processing.